Epidemiological indicators of Chagas disease in the metropolitan region of Salvador, Bahia, Brazil

ABSTRACT Background: Chagas disease (CD) is caused by Trypanosoma cruzi and transmitted by triatomines. Historical information from the 20th century demonstrates T. cruzi records in the metropolitan region of Salvador (MRS), the third largest urban agglomeration in the Brazilian Northeast and the eighth largest in Brazil, an area with intense migratory activity from CD-endemic regions. Therefore, this study aimed to evaluate CD indicators (prevalence and mortality) in the MRS. Methods: A mixed ecological and descriptive study was conducted using secondary data. We analyzed data from 2008 to 2015: deaths due to CD, self-reported cases of CD, and blood donors that were non-negative for T. cruzi infection. Results: São Francisco do Conde was one of the municipalities with the highest mortality rates due to CD. The seroprevalence rates varied by year and municipality; those with the highest values were 2008: Vera Cruz, 2009: Mata de São João, 2010: Dias D'Ávila, 2011 and 2015: São Francisco do Conde, 2012: São Sebastião do Passé, and 2013 and 2014: Pojuca. Spatial correlations between the municipalities were not detected. Conclusions: We conclude that CD is present in the MRS. The indicators analyzed in the MRS are below-state-level data. Given the importance of indicator analysis for the surveillance and control of CD at the state and national levels, it is important to strengthen the surveillance program at the municipal level, including the regions classified as low risk for T. cruzi vector transmission.


INTRODUCTION
Chagas disease (CD) is caused by the flagellated protozoan parasite Trypanosoma cruzi (Chagas, 1909), transmitted by the insect vector, triatomine bugs 1 . It is estimated that 6-7 million people are affected by CD worldwide (mainly in Latin American countries) 2 . In Brazil, 1.9-4.6 million people live with the disease; specifically, Bahia has an average of 624 deaths per year, the fourth state with the highest mortality rate from 2010 to 2019 3,4 . In Bahia, there are many records of people with chronic CD, and in the last 10 years, two acute cases have been confirmed only according to records in information systems. Occurrence of CD is probably underreported 4 .
Historically, the prevalence T. cruzi infection was higher in rural areas. However, owing to migratory movements, patients with CD have spread to urban areas. Therefore, most infected people are believed to live in urban areas 6,7 , which requires epidemiological surveillance to understand the extent of the problem and to plan effective prevention and control measures for CD, as well as specialized medical care and treatment for infected patients living in these areas.
Historical records indicate that T. cruzi has been present in the metropolitan region of Salvador (MRS), particularly in the municipality of Mata de São João since the early 20 th century 5 . In the early 1970s, in one of the last research projects in the city of Salvador, 149 specimens of Panstrongylus megistus and 452 specimens of Triatoma rubrofasciata were found in the historic center (Pelourinho). Of these, 16% were infected by T. cruzi 7 . In recent years, triatomines infected with T. cruzi have been identified visiting households in urban areas in fragments of the Atlantic Forest biome in the municipality of Salvador. These studies demonstrated the frequent occurrence of Triatoma tibiamaculata infected with T. cruzi in houses and apartments near deforested areas in several neighborhoods of the city 8,9 . However, there is little information about triatomines in the municipal databases of the health surveillance system in the MRS. Therefore, we decided to study CD in the municipalities of MRS, considering other parameters to provide information to support health managers on the importance of entomological surveillance.
Surveillance activities in Brazil are usually triggered by acute CD cases reported in the Notifiable Diseases Information System (SINAN) 10 , although the number of cases reported in this system has been underreported 11 . Therefore, it is necessary to use other data sources, such as medical assistance, to support public health interventions.
Follow-up of patients with CD in the MRS should be mainly in the primary care of the Public Health System. Severe cases of acute or reactive disease and decompensated chronic cases should be referred to other levels of care and, if necessary, specialized hospitals 12 . Due to diagnostic difficulties in the acute phase of the disease, many cases progress to the chronic form, whose clinical manifestations may be cardiac, digestive, or mixed 10 . Among the neglected tropical diseases in Brazil, CD had the highest proportion of global disease burden in 2016 (29.8% of the total) 13 .
The results of serological screening of blood donors provide important information for CD. This initiative was launched in 1991 by the Southern Cone Initiative with the goal of reducing and eliminating blood transfusion transmission through serological screening of donors from blood banking networks 14 . Blood transfusion transmission is considered the second most common cause of CD in non-endemic industrialized countries, particularly in countries receiving immigrants from Latin America 15 . The prevalence of T. cruzi infection in blood donors is a powerful epidemiological indicator and can be used as an indicator of CD transfusion risk and transmission in an area 14,16 . From 2008 to 2018, the Foundation for Hematology and Hemotherapy of the State of Bahia (HEMOBA) presented 500,256 blood donors. Of these donors, 3,084 (0.62%) tested positive for CD. It was observed that 1,108 (35.9%) of the screened cases corresponded to people living in Salvador 4 .
Primary health care data on the follow-up of patients with CD, serologic testing of blood donors, and mortality from CD may be useful information to identify priority areas for public health interventions. Therefore, this study aimed to evaluate CD indicators (prevalence and mortality) in the municipalities of MRS.

Study area
This study evaluated only CD indicators from the MRS, which includes the capital of the state of Bahia (Salvador) and

Epidemiological data
We analyzed data from 2008 to 2015 using the following variables: (1) deaths due to CD, (2) self-reported cases of CD registered in the Primary Care Information System (SIAB), and (3) blood donors registered as non-negative for T. cruzi infection in the serological screening performed by the HEMOBA Foundation. The samples considered non-negative by the HEMOBA Foundation were those with reactive results for T. cruzi infection. High-sensitivity tests are mandatory for screening for CD. From 1991 to 2015, the HEMOBA used anti-T. cruzi and enzyme-linked immunosorbent assay (ELISA). In February 2015, the HEMOBA began to perform serological screening through chemiluminescence tests with IgG and IgM antibodies. The same test was used in the second screening, and in case of positivity, donors were sent to a referral unit 9 . Data were provided by the Department of Epidemiological Surveillance of the Ministry of Health of the State of Bahia (DIVEP/SESAB) and HEMOBA Foundation.

Data analysis and geoprocessing
Data were analyzed considering the prevalence or mortality of CD per 100,000 inhabitants in each municipality. The rate per 100,000 inhabitants was obtained considering the population of each municipality yearly, according to the IBGE census, through the Basic Care Information and Management website (https://egestorab.saude.gov.br/paginas/acessoPublico/relatorios/ relHistoricoCoberturaAB.xhtml) 18 . For geoprocessing, the geographic information system of QGIS ™ software version 3.20.3 was used to analyze and determine the information patterns. Shapefiles containing the geographic boundaries of the municipalities of MRS were obtained from the IBGE database (https://downloads.ibge.gov.br) 20 . The spatial unit used for georeferencing was the name of the municipality or IBGE geocode. The GeoDa ® (Center for Spatial Data Science, University of Chicago) tool was used to perform a spatial autocorrelation analysis with the values of the prevalence coefficients of the epidemiological variables. Through a spatial statistical analysis considering the average values of the prevalence coefficients of the three previously presented CD indicators, GeoDa software was used to test for spatial autocorrelation through the analysis of the Moran's index during the study period.

Ethics statement
All databases used in this study are available in the public domain and do not allow the identification of individuals. In 2016, a new resolution published by the Brazilian National Health Council abated the need to seek approval from any Institutional Review Board for studies using publicly available secondary data that did not provide identifiable information (http://conselho.saude.gov. br/resolucoes/2016/reso510.pdf).

Death due to Chagas disease
A total of 1,517 deaths due to CD were recorded between 2008 and 2015. The municipalities with the highest mortality rates from CD are listed in Table 1. In 2008, 2009, 2010, and 2013, São Francisco do Conde remained one of the municipalities with the highest mortality rate due to CD, with 23.5, 16, 15.8, and 17.5/100,000 inhabitants, respectively. Other municipalities that also had high mortality rates during the study period were Mata de São João and Candeias (Figure 1).

Self-reported prevalence coefficient Chagas disease/100,000 inhabitants of Chagas disease registered in the primary care information system
Prevalence per 100,000 inhabitants for MRS municipalities can be found in Table 2 (Figure 1).

Seroprevalence coefficient for T. cruzi infection/100,000 HEMOBA Foundation blood donors
Between 2008 and 2015, the total number of blood donors residing in the MRS was 288,281 ( Table 3) We did not find statistical evidence of spatial autocorrelation between municipalities when analyzing the three variables cited. The Moran's index value was 0.064, and the P-value in the pseudosignificance test was 0.42, confirming spatial independence between the municipalities. As shown in Figure 1, there are similarities between deaths due to CD and self-reported cases in many regions and even among blood donors, although, proportionally, infection in blood banks is higher. The municipalities with the highest evidence of CD, according to the variables, were São Francisco do Conde, Mata de São João, and Candeias.

DISCUSSION
Based on the analysis of the three variables investigated in the present study, the municipalities of São Francisco do Conde, Mata de São João, and Candeias showed higher rates of CD, indicating that there is still a risk of transmission in some areas of the MRS in Bahia.
Deaths due to CD were observed in all municipalities of MRS.
Notably, approximately 20.8% of the deaths occurred in a different municipality than the one where the person lived 22 . This could be related to the patient demand for better medical care and hospital infrastructure, which could overwhelm public health administration planning 10 . In addition, there are no official guidelines for recording         In all municipalities of MRS, there were records of self-reported cases of CD. A section on self-reported diseases or conditions can be completed using SIAB application forms. It is possible to register a CD. In this case, community health providers should not require proof of diagnosis 4 , which indicates the need to improve access to diagnosis, specific treatment, and follow-up for patients with CD. In addition, it is not possible to determine the incidence, but only the prevalence, because it is not possible to define whether the cases registered each year are new or recurrent.
Regarding serological screening at the HEMOBA Foundation, there were blood donors who were non-negative for T. cruzi from all municipalities of the MRS, which were recorded as either city of birth and/or residence. The prevalence of T. cruzi infection in blood donors may be an important epidemiological indicator, consolidating its position as a transfusion risk marker for CD and measuring the degree of transmission of the disease in a region 14,[19][20][21][22][23][24] . In Brazil, the incidence of serological reactions resulting from reagent samples for T. cruzi has decreased significantly over the years because of the positive results of triatomine control and improvement in the quality of life of the population in formerly endemic areas 25,26 . The positive serology for T. cruzi from 1987 to 1994 was 0.77-2.22% in Bahia and 0.69-0.88% in northeastern Brazil. The seropositivity in Brazil from 1988 to 1990 was 0.97%, with a decrease in the following years; 0.7-1.1% in 1991, 0.7% in 1993, was, and 0.75% in 1994. From 2008 to 2018, the seroprevalence was 0.62% 14,19 . Evaluation of the distribution of reactivity among the municipalities of MRS showed that Salvador had the most reactive serologies compared with the other municipalities. This could be a consequence of migration from endemic areas to the city of Salvador, either within or outside Bahia. This study has methodological limitations common to studies based on secondary data, particularly regarding the underreporting of deaths due to CD. In addition, despite all efforts to include entomological indicators, this was not possible because triatomines were not recorded in most municipalities. It is important to increase health communication for CD on social media and keep health professionals informed to make them aware of the suspicion, diagnosis, treatment, and follow-up of patients with CD. Thus, professionals can monitor the disease and collect data for surveillance systems.
The data of this study suggest that more attention should be paid to CD monitoring systems and that surveillance of CD is necessary for the municipalities of MRS and others 8,9 . Conducting studies to identify social, economic, and environmental factors involved in the epidemiological context of CD will help develop measures to control the infection and improve the documentation of cases in these localities. In addition, new methods should be applied, such as analyzing and estimating the underreporting of cases/deaths, to update the risk classification for CD in the MRS.